EP2675786B1 - Ester derivatives of bimatoprost compositions and methods - Google Patents

Ester derivatives of bimatoprost compositions and methods Download PDF

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Publication number
EP2675786B1
EP2675786B1 EP12705582.0A EP12705582A EP2675786B1 EP 2675786 B1 EP2675786 B1 EP 2675786B1 EP 12705582 A EP12705582 A EP 12705582A EP 2675786 B1 EP2675786 B1 EP 2675786B1
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Prior art keywords
compound
bimatoprost
iva
compounds
unsubstituted
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German (de)
English (en)
French (fr)
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EP2675786A1 (en
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David F. Woodward
Jenny W. Wang
Michael E. Garst
Robert M. Burk
Todd S. Gac
Neil J. POLOSO
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Allergan Inc
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Allergan Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention is directed to, inter alia, prodrugs of bimatoprost, formulations containing prodrugs of bimatoprost, and uses of bimatoprost prodrugs as set forth in the claims.
  • Bimatoprost isomer [(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxy-5-phenylpent-1-enyl)cyclopentyl)-N-ethylhept-5-enamide] (sold under the name Lumigan® by Allergen, Inc., Irvine, CA), was initially developed for the treatment of a variety of diseases or disorders, including ocular hypertension and glaucoma. See U.S. Pat. Nos. 5,607,978 , 5,688,819 , 6,403,649 , 8,017,655 .
  • bimatoprost results in hypertrichosis (i.e., increased hair growth) in treated regions.
  • results of administration of bimatoprost include altered differentiation, number, length, thickness, curvature and pigmentation
  • WO03/066008 discloses the use of bimatoprost for enhancing hair growth.
  • bimatoprost including prodrugs, which provide efficacy in the treatment of a variety of diseases or disorders, such as lowering intraocular pressure, hair loss, inflammatory diseases and disorders of the skin, and for the reduction of local adipose deposits.
  • diseases or disorders such as lowering intraocular pressure, hair loss, inflammatory diseases and disorders of the skin, and for the reduction of local adipose deposits.
  • the present disclosure provides a compound with the structure of Formula (I), or derivative, isomer, or enantiomer thereof.
  • R 1 is hydrogen or R 1a C(O)-.
  • R 2 is hydrogen or R 2a C(O)-.
  • R 3 is hydrogen or R 3a C(O)-.
  • R 1a , R 2a and R 3a are independently substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, or substituted or unsubstituted aryl.
  • R 4 and R 5 are independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl. In some embodiments, at least one of R 1 , R 2 and R 3 is not hydrogen.
  • the present invention provides a compound having the structure of Formula (IVa), (IIIb) and (IVb) or isomer, or enantiomer thereof as set forth in the claims.
  • the present disclosure provides a pharmaceutical composition.
  • the pharmaceutical composition includes a pharmaceutically acceptable excipient and a compound with the structure of Formula (I) or derivative, isomer, or enantiomer thereof.
  • R 1 is hydrogen or R 1a C(O)-.
  • R 2 is hydrogen or R 2a C(O)-.
  • R 3 is hydrogen or R 3a C(O)-.
  • R 1a , R 2a and R 3a are independently substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, or substituted or unsubstituted aryl.
  • R 4 and R 5 are independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl. In some embodiments, at least one of R 1 , R 2 and R 3 is not hydrogen.
  • the present invention provides a pharmaceutical composition including a pharmaceutically acceptable excipient and the compound having the structure of Formula (IVa), (IIIb) and (IVb) as set forth in the claims.
  • a compound having the structure of Formula (IVa), (IIIb) and (IVb) for use in a method for inducing hair growth includes administering to a subject in need thereof a therapeutically effective amount of said compound
  • the compound may be provided as part of a pharmaceutical composition as described herein and set forth in the claims.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched chain, or combination thereof, which may be fully saturated (referred to herein as a "saturated alkyl"), mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated ( i.e. C 1 -C 10 means one to ten carbons).
  • all alkyls set forth as a substituent of the compounds provided herein are saturated alkyls.
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • n "alkoxy” is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).
  • An “alkylthio” is an alkyl attached to the remainder of the molecule via an sulfur linker (-S-).
  • haloalkoxy is an alkoxy substituted with a halogen.
  • halogen is a fluoro
  • alkyl includes saturated alkyl, alkenyl and alkynyl.
  • a saturated alkyl may have from 1 to 10 or 1 to 6 carbon atoms.
  • alkenyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched hydrocarbon chain (e.g., two to ten, or two to six carbon atoms) having one or more double bonds.
  • alkynyl groups examples include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl).
  • alkynyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched hydrocarbon chain (e.g., two to ten or two to six carbon atoms) having one or more triple bonds.
  • alkynyl groups include, but are not limited to, ethynyl, 1- and 3-propynyl, 3-butynyl.
  • Aminocarbonyl means a -CONRR' radical where R is independently hydrogen, unsubstituted alkyl, or alkyl substituted with a substituent group and R' is hydrogen, unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted cycloalkylalkyl, unsubstituted aryl, unsubstituted aralkyl, unsubstituted heteroaryl, unsubstituted heteroaralkyl, unsubstituted heterocycloalkyl, unsubstituted heterocyclylalkyl, or alkyl substituted with a substituent group, each as defined herein and wherein the aryl, heteroaryl, or heterocyclyl ring either alone or part of another group e.g., aralkyl, is optionally substituted with one, two, or three substituent group(s).
  • aminocarbonyl means a -CONRR' radical where R is independently hydrogen,
  • alkylene by itself or as part of another substituent means a divalent radical derived from an alkyl, alkenyl, or alkynyl as exemplified by methylene, ethylene, -CH 2 CH 2 CH 2 CH 2 -, vinylene.
  • amino as used herein means a -NH 2 .
  • carboxy as used herein means -COOH (including pharmaceutically acceptable salts thereof).
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si or S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH 2 -CH 2 -S-CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroatoms can also occupy either or both of the chain termini ( e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino).
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom
  • cycloalkyl and heterocycloalkyl represent, unless otherwise stated, non-aromatic cyclic versions of “alkyl” and “heteroalkyl”, respectively (e.g., having 4 to 8 ring atoms). Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Heterocycloalkyls may include one or two ring heteroatoms selected from N, O, or S(O) n' , where n' is an integer from 0 to 2, the remaining ring atoms being carbon.
  • the heterocycloalkyl or cycloalkyl ring is optionally fused to one or more aryl or heteroaryl rings as defined herein (e.g., where the aryl and heteroaryl rings are monocyclic).
  • the heterocycloalkyl or cycloalkyl ring fused to monocyclic aryl or heteroaryl ring may be referred to in this Application as "bicyclic heterocycloalkyl" ring or a "bicyclic cycloalkyl” ring.
  • one or two ring carbon atoms in the heterocycloalkyl ring can optionally be replaced by a -CO- group.
  • heterocycloalkyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, dihydroindolyl.
  • heterocycloalkyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic.
  • the heterocycloalkyl group contains at least one nitrogen atom, it may also be referred to herein as heterocycloamino and is a subset of the heterocycloalkyl group.
  • heterocycloalkyl group When the heterocycloalkyl group is a saturated ring and is not fused to aryl or heteroaryl ring as stated above, it may be referred to herein as a saturated monocyclic heterocycloalkyl.
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl.
  • heterocycloalkyl examples include, but are not limited to, 1 -(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 - piperazinyl, 2-piperazinyl.
  • a "cycloalkylene” and a "heterocycloalkylene,” alone or as part of another substituent means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.
  • Heterocycloamino as used herein means a saturated or unsaturated monovalent monocyclic group (e.g., having 4 to 8 ring atoms) in which one or more (e.g., 2) ring atoms is a heteroatom selected from N, O, or S(O) n" , where n" is an integer from 0 to 2, the remaining ring atoms being carbon provided that at least one of the ring atoms is nitrogen. Additionally, one or more (e.g., 2) ring carbon atoms in the heterocycloamino ring can optionally be replaced by a -CO- group.
  • heterocycloamino ring When the heterocycloamino ring is unsaturated it can contain one or more (e.g., two) ring double bonds provided that the ring is not aromatic. Unless otherwise stated, the heterocyloamino ring can optionally be substituted with one, two, or three substituents (e.g., independently selected from saturated unsubstituted alkyl, hydroxyl, saturated unsubstituted alkoxy, amino, saturated unsubstituted alkylamino, or saturated unsubstituted dialkylamino). Heterocycloamino is a subset of heterocycle defined above.
  • halo or halogen
  • haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is meant to include, but not be limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl.
  • acyl means -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
  • aryl means, unless otherwise stated, an aromatic substituent which can be a single ring or multiple rings (preferably from 1 to 3 rings) which may be fused together (i.e. a fused ring aryl) or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring (e.g., phenyl, 1-naphthyl, 2-naphthyl, or 4-biphenyl).
  • heteroaryl refers to aryl groups (or rings) that contain one or more (e.g., 4) heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized, the remaining ring atoms being carbon.
  • the heteroaryl may be a monovalent monocyclic, bicyclic, or tricyclic (e.g., monocyclic or bicyclic) aromatic radical of 5 to 14 (e.g., 5 to 10) ring atoms where one or more, (e.g., one, two, or three or four) ring atoms are heteroatom selected from N, O, or S.
  • Examples include, but are not limited to, thienyl, isoindolyl, benzoxazolyl, pyridazinyl, triazolyl, tetrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,
  • heteroaryl includes fused ring heteroaryl groups (i.e. multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring).
  • a 5,6-fused ring heteroaryl refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,6-fused ring heteroaryl refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,5-fused ring heteroaryl refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • An "arylene” and a “heteroarylene,” alone or as part of another substituent means a divalent radical derived from an aryl and heteroaryl, respectively.
  • arylalkyl and heteroarylalkyl is meant to include those radicals in which an aryl group or a heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl) including those alkyl groups in which a carbon atom ( e.g., a methylene group) has been replaced by, for example, an oxygen atom ( e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl).
  • alkyl group e.g., benzyl, phenethyl, pyridylmethyl
  • an oxygen atom e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl.
  • oxo as used herein means an oxygen that is double bonded to a carbon atom.
  • carbonyl as used herein refers to a -C(O)- group.
  • heterocycloalkyl group optionally substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocycloalkyl group is substituted with an alkyl group and situations where the heterocycloalkyl group is not substituted with alkyl.
  • alkylsulfonyl as used herein means a moiety having the formula -S(O 2 )-R', where R' is an alkyl group as defined above. R' may have a specified number of carbons (e.g., "C 1 -C 4 alkylsulfonyl").
  • alkyl e.g., "alkyl,” “heteroalkyl,” “aryl” and “heteroaryl” are meant to include both substituted and unsubstituted forms of the indicated radical unless stated otherwise.
  • R', R", R'" and R" each independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
  • each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring.
  • -NR'R is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and - CH 2 CF 3 ) and acyl ( e.g ., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 ).
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR') q -U-, wherein T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'- or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X'-(C"R"') d -, where s and d are independently integers of from 0 to 3, and X' is - O-, -NR'-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR'-.
  • R, R', R" and R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • heteroatom or “ring heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
  • a “substituent group,” as used herein, means a group selected from the following moieties:
  • a “size-limited substituent” or “ size-limited substituent group,” as used herein means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 4 -C 8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4 to 8 membered heterocycloalkyl.
  • a “lower substituent” or “ lower substituent group,” as used herein means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 5 -C 7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to 7 membered heterocycloalkyl.
  • derivative in the context of a compound disclosed herein refers to a compound afforded by chemical modification, e.g., by the bonding of one or more substituent groups as described herein.
  • salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids
  • salts of amino acids such as arginate
  • salts of organic acids like glucuronic or galactunoric acids. See e.g., Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19 ). Additional information on suitable pharmaceutically acceptable salts can be found in REMINGTON'S PHARMACEUTICAL SCIENCES, 17th ed., Mack Publishing Company, Easton, PA, 1985 . Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the compounds disclosed herein may exist as salts.
  • salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures), succinates, benzoates and salts with amino acids such as glutamic acid.
  • These salts may be prepared by methods known to those skilled in the art.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • prodrug is used according to its plain ordinary meaning and is intended to mean compounds that require a chemical or enzymatic transformation in order to release the active parent drug in vivo prior to producing a pharmacological effect.
  • the compounds of the present invention may have asymmetric centers and/or geometric isomers.
  • Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. All chiral, diastereomeric, racemic forms are within the scope of this invention, unless the specific stereochemistry or isomeric form is specifically indicated. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this invention. Additionally, as used herein the term alkyl includes all the possible isomeric forms of the alkyl group albeit only a few examples are set forth.
  • cyclic groups such as aryl, heteroaryl, heterocycloalkyl
  • cyclic groups such as aryl, heteroaryl, heterocycloalkyl
  • they include all the positional isomers albeit only a few examples are set forth.
  • all polymorphic forms, including amorphous form, and hydrates of a compound disclosed herein are within the scope of this invention.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, tautomers, geometric isomers and individual isomers are encompassed within the scope of the present invention, as are enantiomers.
  • the compounds of the present invention do not include those which are known in the art to be too unstable to synthesize and/or isolate.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
  • R-substituted e.g., R 7 -substituted
  • R 7 substituent of a compound provided herein
  • R 7 substituent of a compound provided herein is "R-substituted"
  • R 7 substituent of a compound provided herein is "R-substituted"
  • R 7 it is meant that the substituent is substituted with one or more of the named R groups (e.g., R 7 ) as appropriate. Each appearance of the substituent may be different. In some embodiments, the substituent is substituted with only one of the named R groups.
  • Each of the numbered R substituents provided herein may be alternatively referred to as a primed number such as a first prime ('), a second prime ("), a third prime ("') and so on.
  • R 7 may be alternatively referred to as R 7' , R 7" , R 7'" and so on.
  • R 7 and R 7' are independently chosen from the same Markush group definition.
  • a “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient.
  • treating refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation.
  • the certain methods presented herein successfully treat cancer by decreasing the incidence of cancer, in inhibiting its growth and or causing remission of cancer.
  • an “effective amount” of a compound is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease. Where recited in reference to a disease treatment, an “effective amount” may also be referred to as a “therapeutically effective amount.”
  • a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • a “prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) a disease, disorder or condition, or reducing the likelihood of the onset (or reoccurrence) of a disease, disorder or condition or symptoms thereof.
  • the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a prophylactically effective amount may be administered in one or more administrations.
  • topical in the context of methods described herein relates in the customary sense to the administration of a compound or pharmaceutical composition which is incorporated into a suitable pharmaceutical carrier and administered at a topical treatment site of a subject.
  • topical pharmaceutical composition includes those pharmaceutical forms in which the compound is administered externally by direct contact with a topical treatment site, e.g., the eye or the skin.
  • topical ocular pharmaceutical composition refers to a pharmaceutical composition suitable for administering directly to the eye.
  • topical epidermal pharmaceutical composition refers to a pharmaceutical composition suitable for administering directed to the epidermal layer of the skin, e.g., the palpebra, the supercilium, the scalp, or the body.
  • topical administering refers to administering externally by direct contact with a topical treatment site.
  • topical epidermal administering refers to administering externally by direct contact with the epidermis.
  • topical ocular administering refers to administering externally by direct contact with the eye.
  • Methods of administering to the skin may include “topical palpebra administering” which refers to administering to the palpebra (i.e., eyelid) and especially the portion of the palpebra from which the cilia (i.e., eyelashes) grow.
  • Methods of administering to the skin further include “topical supercilium administering” which refers to administering to the supercilium (i.e., the ridge above the eye) from which the supercilia (i.e., eyebrows) grow.
  • Methods of administering to the skin further include “topical scalp administering” which refers to administering directly to the scalp.
  • Methods of administering to the skin further include “topical body administering” which refers to administering directly to parts of the body excluding the scalp.
  • ointments Conventional pharmaceutical forms for this purpose include ointments, liniments, creams, shampoos, lotions, pastes, jellies, sprays, aerosols, and may be applied in patches or impregnated dressings depending on the part of the body to be treated.
  • the term "ointment” embraces formulations (including creams) having oleaginous, water-soluble and emulsion-type bases, e.g., petrolatum, lanolin, polyethylene glycols, as well as mixtures of these.
  • piliation refers in the customary sense to the formation and growth of hair. Accordingly, piliation and “hair growth” are used synonymously herein.
  • Embodiments of the compound of Formula (II) include compounds with structure of one of Formulae (IIa)-(IIc) following: and
  • Embodiments of the compound with structure of Formula (III) include compounds with structure of one of Formulae (IIIa)-(IIId) following:
  • a pharmaceutical composition including a pharmaceutically acceptable excipient and a compound with structure of Formula (IIIb) (IVa), or (IVb).
  • the compound has the structure of Formula (IVb).
  • the pharmaceutical composition is a solution, emulsion, gel or foam. In one embodiment, the pharmaceutical composition is a solution. In one embodiment, the pharmaceutical composition is an emulsion. In one embodiment, the pharmaceutical composition is a gel. In one embodiment, the pharmaceutical composition is a foam.
  • the pharmaceutical composition is a topical pharmaceutical composition. In one embodiment, the pharmaceutical composition is a topical epidermal pharmaceutical composition.
  • compositions contemplated herein can be prepared and administered in a variety of forms including solution, emulsion, gel or foam. Accordingly, pharmaceutical compositions contemplated herein include a pharmaceutically acceptable carrier or excipient and one or more compounds described herein.
  • “Solution” refers in the customary sense to a liquid pharmaceutical composition in which a compound (e.g., a compound described herein), is at least partially dissolved, preferably fully dissolved, and which can be administered as a liquid.
  • Emmulsion refers in the customary sense to a mixture of two or more immiscible liquids, one compound (e.g., a compound described herein or solution thereof) being dispersed through the other compound (e.g., a carrier as described herein).
  • Gel refers in the customary sense to a highly viscous solution, emulsion, or colloidal suspension of a compound within a continuous fluid phase resulting in a viscous semirigid fluid.
  • Colloid refers in the customary sense to a composition which includes a continuous medium throughout which are distributed small particles which do not settle under the influence of gravity.
  • Foam refers in the customary sense to a composition which includes a continuous medium (i.e., solution, emulsion, gel) through which gas (e.g., air) is dispersed.
  • compositions contemplated herein may be prepared by combining a therapeutically effective amount of at least one compound as described herein as an active ingredient in combination with one or more conventional pharmaceutically acceptable excipients, and by preparation of unit dosage forms suitable for topical use.
  • the therapeutically efficient amount typically is between about 0.0001 and about 5% (w/v), preferably about 0.001 to about 1.0% (w/v) in liquid formulations which include solutions, emulsions, gels and foams.
  • Pharmaceutical admixtures suitable for use in the present invention include those described, for example, in PHARMACEUTICAL SCIENCES (17th Ed., Mack Pub. Co., Easton, PA ) and WO 96/05309 .
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such co-solvents are typically employed at a level between about 0.01 % and about 2% by weight.
  • Viscosity greater than that of simple aqueous solutions may be desirable to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation, and/or otherwise to improve the formulation.
  • Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing.
  • Such agents are typically employed at a level between about 0.01% and about 2% by weight.
  • compositions of the present invention may additionally include components to provide sustained release and/or comfort.
  • Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920 ; 5,403,841 ; 5,212,162 ; and 4,861,760 .
  • US Patent application publication No. US 2011-0124736 A1 also corresponding to US Patent application serial no. 12/940,711 .
  • solutions are prepared using a physiological saline solution as a major vehicle.
  • the pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential.
  • the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
  • buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
  • Preferred preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate.
  • a preferred surfactant is, for example, Tween 80.
  • various preferred vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose cyclodextrin and purified water.
  • Tonicity adjustors may be added as needed or convenient. They includesalts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
  • An ophthalmically acceptable antioxidant for use in the present invention includessodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
  • excipient components which may be included in the ophthalmic preparations are chelating agents.
  • the preferred chelating agent is edentate disodium, although other chelating agents may also be used in place of or in conjunction with it.
  • the ophthalmic formulations of the present invention are conveniently packaged in forms suitable for metered application, such as in containers equipped with a brush, to facilitate application to the palpebra.
  • an application brush is disposed within a unit dose vial.
  • Vials suitable for unit dose application are usually made of suitable inert, non-toxic plastic material, and generally contain between about 0.5 and about 15 ml solution, emulsion, gel or foam.
  • One package may contain one or more unit doses.
  • Preservative-free solutions are often formulated in non-resealable containers containing up to about ten, preferably up to about five units doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops.
  • the active compounds can be formulated in aqueous solutions, creams, ointments or oils exhibiting physiologically acceptable osmolarity by addition of pharmacologically acceptable buffers and salts.
  • Such formulations may or may not, depending on the dispenser, contain preservatives such as benzalkonium chloride, chlorhexidine, chlorobutanol, parahydroxybenzoic acids and phenylmercuric salts such as nitrate, chloride, acetate, and borate, or antioxidants, as well as additives like EDTA, sorbitol, boric acid etc. as additives.
  • aqueous solutions may contain viscosity increasing agents such as polysaccharides, e.g., methylcellulose, mucopolysaccharides, e.g., hyaluronic acid and chondroitin sulfate, or polyalcohol, e.g., polyvinylalcohol.
  • viscosity increasing agents such as polysaccharides, e.g., methylcellulose, mucopolysaccharides, e.g., hyaluronic acid and chondroitin sulfate
  • polyalcohol e.g., polyvinylalcohol.
  • slow releasing gels and matrices may also be employed as well as soluble and insoluble ocular inserts, for instance, based on substances forming in-situ gels.
  • the compound can be advantageously formulated using ointments, creams, liniments or patches as a carrier of the active ingredient.
  • these formulations may or may not contain preservatives, depending on the dispenser and nature of use.
  • preservatives include those mentioned above, and methyl-, propyl-, or butyl-parahydroxybenzoic acid, betain, chlorhexidine, benzalkonium chloride.
  • matrices for slow release delivery may also be used.
  • the compounds are applied repeatedly for a sustained period of time topically on the part of the body to be treated, for example, the eyelids, eyebrows, body or scalp.
  • the preferred dosage regimen will generally involve regular administration for a period of treatment of at least one month, more preferably at least three months, and most preferably at least six months.
  • the regular administration can be 1, 2, 3, 4 or even more times per day.
  • Formulations for use in the methods and pharmaceutical compositions disclosed herein include Formulation A, provided in Table 1 following.
  • active component refers to bimatoprost or a compound as described herein (e.g., a compound with structure of Formula (IIIb), (IVa), or (IVb)or derivative, isomer or enantiomer thereof).
  • q.s i.e., quantum satis
  • water q.s. to 100% refers to sufficient water to bring the formulation to 100%. Table 1.
  • Formulation A Ingredient Amount Active component (% w/w) 0.03 Glycerin (% w/w) 2.0 Propylene Glycol (% w/w) 10.0 Diethylene Glycol Monoethyl Ether (% w/w) 10.0 Ethyl Alcohol (% w/w) 30.0 Carbomer Ultrez 10 (% w/w) 0.15 Triethanolamine (% w/w) 0.16 Purified Water q.s. to 100% pH ⁇ 7
  • Additional formulations for use in the methods and pharmaceutical compositions disclosed herein include formulations exemplified in Tables 2 and 3 following, wherein the amount of each component (i.e., % w/w) is included within the indicated range.
  • Table 2 Exemplary Formulations Ingredient Range (% w/w) Active component 0.001 - 3.00 Glycerin 1.0 - 4.0 Propylene Glycol 5.0 - 15.0 Diethylene Glycol Monoethyl Ether 5.0 - 15.0 Ethyl Alcohol 25.0-35.0 Carbomer Ultrez 10 0.05 - 0.30 Triethanolamine 0.05 - 0.30 Purified Water q.s. to 100% Table 3.
  • Exemplary Formulations Ingredient Range (% w/w) Active component 0.01 - 0.1 Glycerin 0.001 - 4.0 Propylene Glycol 0.5 - 20.0 Diethylene Glycol Monoethyl Ether 0.5 - 20.0 Ethyl Alcohol 0.5 - 45.0 Carbomer Ultrez 10 0.1 - 0.30 Triethanolamine 0.1 - 0.32 Purified Water q.s. to 100%
  • compositions provided herein include compositions wherein the active ingredient (i.e. a compound with structure of Formula (IIIb), (IVa), or (IVb) or derivative, isomer or enantiomer thereof) is contained in a therapeutically effective amount.
  • the active ingredient i.e. a compound with structure of Formula (IIIb), (IVa), or (IVb) or derivative, isomer or enantiomer thereof
  • the actual amount effective for a particular application will depend, inter alia, on the disease, disorder or condition being treated.
  • the dosage and frequency (single or multiple doses) of compound administered can vary depending upon a variety of factors, including route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease, disorder or condition being treated (e.g., the degree of hair loss); presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen.
  • Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of the invention.
  • Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring piliation and adjusting the dosage upwards or downwards, as described herein.
  • Dosages may be varied depending upon the requirements of the subject and the compound being employed.
  • the dose administered to a subject should be sufficient to effect a beneficial therapeutic response in the patient over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side effects. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.
  • Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
  • an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is entirely effective to treat the clinical symptoms demonstrated by the particular patient.
  • This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration, and the toxicity profile of the selected agent.
  • the daily amount of compound for treatment of the palpebra is about 0.1 ng to about 100 mg per eyelid.
  • the dose to be applied is in the range of about 0.1 ng to about 100 mg per day, more preferably about 1 ng to about 10 mg per day, and most preferably about 10 ng to about 1 mg per day depending on the compound and the formulation.
  • the compound may be administered once or several times daily with or without antioxidants.
  • an amount of the active compound in a pharmaceutical composition is about 1x10 -7 to 50% (w/w), about 0.001 to 50% (w/w), about 0.01 to 50% (w/w), about 0.1 to 50% (w/w), or about 1 to 50% (w/w).
  • the amount of the active compound in a pharmaceutical composition is about 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 3.0%, 4.0% and 5.0% w/w.
  • an effective amount, e.g., a therapeutically effective amount, of the active compound in a pharmaceutical composition is afforded at a concentration of about 1x10 -7 to 50% (w/w), about 0.001 to 50% (w/w), about 0.01 to 50% (w/w), about 0.1 to 50% (w/w), or about 1 to 50% (w/w).
  • the therapeutically effective amount of the active compound in a pharmaceutical composition is about 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% and 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 3.0%, 4.0% and 5.0% w/w.
  • the ratio between toxicity and therapeutic effect for a particular compound is its therapeutic index and can be expressed as the ratio between LD 50 (the amount of compound lethal in 50% of the population) and ED 50 (the amount of compound effective in 50% of the population).
  • LD 50 the amount of compound lethal in 50% of the population
  • ED 50 the amount of compound effective in 50% of the population.
  • Compounds that exhibit high therapeutic indices are preferred.
  • Therapeutic index data obtained from cell culture assays and/or animal studies can be used in formulating a range of dosages for use in humans.
  • the dosage of such compounds preferably lies within a range of plasma concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • compounds having Formula (IVa), (IIIb) or (IVb) or a pharmaceutical composition comprising including a compound having Formula (IVa), (IIIb) or (IVb) for use in a method for inducing hair growth (e.g., piliation).
  • the method includes administering to a subject in need thereof a therapeutically effective amount of a compound provided herein (i.e. a compound with structure of Formula (IIIb) (IVa), or (IVb) or derivative, isomer or enantiomer thereof).
  • the compound may be provided as part of a pharmaceutical composition as described herein.
  • the subject suffers from alopecia such that the method of inducing hair growth is a method for treating alopecia.
  • the subject is in need of hair growth of the cilia, the supercilium, scalp pili or body pili such that the method of inducing hair growth is a method for inducing growth of the cilia, the supercilium, scalp pili or body pili or the subject, respectively.
  • the subject is in need of hair growth of the cilia.
  • the subject is in need of hair growth of the supercilium.
  • the subject is in need of hair growth of scalp pili.
  • the subject is in need of hair growth of body pili.
  • the administering is topical administering. In one embodiment, the administering is topical epidermal administering.
  • the administering is topical palpebra administering, topical supercilium administering, topical scalp administering, or topical body administering. In one embodiment, the administering is topical palpebra administering. In one embodiment, the administering is topical supercilium administering. In one embodiment, the administering is topical scalp administering. In one embodiment, the administering is topical body administering.
  • the administering is topical scalp administering.
  • the composition is a foam.
  • the administering is topical palpebra administering.
  • the composition is administered from a unit dose vial (e.g., by an application brush disposed within a unit dose vial).
  • the subject is a mammalian subject. In other embodiments the subject is a domesticated animal such as a domesticated mammal. In other embodiments, the subject is a human subject (e.g., a patient).
  • Compounds useful in the methods provided here include those with structure of Formula (IIIb), (IVa), or (IVb) or derivative, isomer or enantiomer thereof.
  • the compound has the structure of Formula (IVa). In one embodiment, the compound has the structure of Formula (IIIb). In one embodiment, the compound has the structure of Formula (IVb).
  • the compound is provided within a pharmaceutical composition such as a solution, emulsion, gel or foam.
  • a pharmaceutical composition such as a solution, emulsion, gel or foam.
  • the pharmaceutical composition is a solution.
  • the composition is an emulsion.
  • the composition is a gel.
  • the composition is a foam.
  • Figs. 1A-1B , 2A-2B , and 3A-3B depict histograms of relative concentrations of test compounds (arbitrary scale) at zero time or 80-days.
  • Fig. 1A depicts a histogram of the stability profile of Compound IVa as a function of pH and temperature.
  • Fig. 1B depicts a histogram of the formation of bimatoprost as a function of pH and temperature after 80-days for Compound IVa.
  • Fig. 2A depicts a histogram of the stability profile of Compound IVb as a function of pH and temperature.
  • Fig. 2B depicts a histogram of the formation of bimatoprost as a function of pH and temperature after 80-days for Compound IVb.
  • Fig. 3A depicts a histogram of the stability profile of Compound IIIb as a function of pH and temperature.
  • Fig. 3B depicts a histogram of the formation of bimatoprost as a function of pH and temperature after 80-days for Compound IIIb.
  • Test system was the reconstructed human epidermis (RHE), as known in the art. Single dosing was employed, and endpoints were evaluated as a function of time up to 24-hrs. Endpoints were tissue viability and IL-1 ⁇ , release.
  • RHE human epidermis
  • Test compounds included Compounds IVa (0.03%), IIIb (0.03%), IVb (0.03%), bimatoprost (0.03%), minoxidil (5%, foam), and minoxidil (5%, solution).
  • Administration of Compounds IVa, IIIb, IVb and bimatoprost employed the vehicle of Formulation A. See Table 1 above.
  • Administration of minoxidil employed minoxidil vehicle with formulation 20% H 2 O, 50% propylene glycol, and 30% ethanol.
  • mice Female rats were administered either vehicle or one of Compounds IVa, IIIb, or IVb daily for 8 days.
  • the administered dose was 3 mg/kg/day, at a concentration of 3 mg/mL.
  • Observed data were body weight, viability, food consumption, and dermal observation (skin reaction grading), as known in the art.
  • the vehicle was Formulation A. See Table 1 above.
  • CDS Cellular dielectric spectroscopy
  • bimatoprost interacts with HHDPC to provide a characteristic change in cell impedance which is understood to correlate with receptor binding.
  • Comparative Compound IVc and Compound IVb were not observed to provide a change in cell impedance under the conditions of the assay.
  • Fig. 4A depicts a histogram of the day of onset of hair growth
  • Fig. 4B depicts the day of full hair growth for (A) vehicle; (B) 0.03% bimatoprost; (C) 0.03% Comparative Compound IIc; (D) 0.03% Comparative Compound IIa; and (E) 0.03% Comparative Compound IIIa.
  • Fig. 5A depicts a histogram of the day of onset of hair growth
  • Fig. 5B depicts the day of full hair growth for (A) vehicle; (B) 0.03% bimatoprost; (C) 0.03% Comparative Compound IIId; and (D) 0.03% Compound IVa.
  • Fig. 6A depicts a histogram of the day of onset of hair growth
  • Fig. 6B depicts the day of full hair growth for (A) vehicle; (B) 0.03% bimatoprost; (C) 0.03% Compound IIIb; (D) 0.03% Compound IIIb; (E) 0.03% Comparative Compound IVc; and (F) 0.03% Comparative Compound IIIc.
  • Fig. 7A depicts a histogram of the day of onset of hair growth
  • Fig. 7B depicts the day of full hair growth for (A) vehicle (Formulation A); (B) 0.03% bimatoprost; (C) 0.03% Compound IVa; (D) 0.03% Compound IIIb; and (E) 0.03% Compound IVb.
  • Fig. 8A depicts a histogram of the day of onset of hair growth
  • Fig. 8B depicts the day of full hair growth for (A) vehicle; (B) 0.03% bimatoprost; (C) 0.03% Compound IIIb; and (D) 0.03% Compound IVb.
  • Fig. 9A depicts a histogram of the day of onset of hair growth
  • Fig. 9B depicts the day of full hair growth for (A) vehicle; (B) 0.3% bimatoprost; (C) 0.1% bimatoprost; (D) 0.03% bimatoprost; and (E) 0.03% Compound IVa.
  • Compound IVa demonstrates pharmacological efficacy greater than bimatoprost in the mouse model of hair regrowth using a vehicle formulation of 50% propylene glycol, 30% ethanol, 20% water. Moreover, Compound IVa demonstrates pharmacological efficacy greater than bimatoprost in this model using a vehicle formulation of Formulation A. Within statistical significance limits, Compounds IIIb and IVb provide approximately equivalent efficacy in this model with respect to bimatoprost using a vehicle formulation of Formulation A.
  • Treatment groups (1) vehicle; (2) 0.03% Compound IVa; (3) 0.03% Compound IIIb; (4) 0.03% Compound IVb; (5) 0.03% bimatoprost.
  • Treatment dosing dermal daily application of ⁇ 60uL test compound solution . Blood and skin pharmacokinetic time points were obtained at day 1 (1, 4, 8 and 24-hrs post-dose); day 2 (24-hrs post-dose); day 14 (24-hrs post-dose); and day 42 (28 days post day 14 dose). Bioanalysis employed LC/MS-MS.
  • Fig. 11A depicts mean concentration of bimatoprost and Compounds IVa, IIIb and IVb in the skin.
  • Fig. 11B depicts mean concentration of bimatoprost at the equivalent time points. Bimatoprost, and Compounds IVa, IIIb and IVb were most undetectable in the systemic circulation at all measured time points.
  • both Compound IVa and Compound IVb afford bimatoprost when incubated with human cadaver skin. Rate of formation: Compound IVa (1.32 pmol/min/mg); Compound IVb (5.59 pmol/min/mg).
  • Test material Dermatomed ex vivo human cadaver posterior trunk skin on 1.0 cm 2 Franz diffusion chamber as known in the art.
  • Test size 3 skin donors (40 year old African American, 60 year old Caucasian, 72 year old Caucasian, obtained from New York Firefighters Skin Bank), 3 replicates per donor per formulation.
  • Test formulations 0.03% active agent (Compound IVa, Compound IIIb, Compound IVb) in Formulation A; control formulation: bimatoprost at 0.03% in Formulation A.
  • Dosing regimen receptor fluid at 2, 4, 24, and 48 hrs; SC/epidermis and dermis at 48 hrs.
  • Sample analysis LC/MS-MS to detect bimatoprost and Compounds IVa, IIIb and IVb.
  • Fig. 15A Skin Distribution and Conversion to Bimatoprost.
  • Fig. 15B depicts a histogram of skin retention per agent in the dermis. It is observed that the amount of active agent (Compounds IVa, IIIb and IVb) in the upper third of the dermis is less than observed for bimatoprost.
  • Compounds IVa, IIIb and IVb are more permeable than bimatoprost, with increased bimatoprost concentration in the receptor chamber solution.
  • Compounds IVa, IIIb and IVb are distributed into SC/Epidermis/Upper dermis to the same extent as bimatoprost, but these active agents demonstrate less retention than bimatoprost in the upper third of the dermis.
  • bimatoprost and prodrugs thereof were to penetrate the skin through the semi-liquid sebum phase to the hair follicle, then prodrugs having sebum-water partitioning greater than bimatoprost may achieve greater hair growth efficacy than observed with bimatoprost.
  • Artificial sebum was prepared as follows: 15% (w/w) squalene, 15% spermaceti, 10% coconut oil, 1.5% oleic acid, 5% palmitic acid, 2.4% cholesterol oleate, 10% paraffin wax, 10% olive oil, 25% cottonseed oil, 5% palmitoleic acid, 1.2% cholesterol.
  • the melting point of the semi-liquid was 37 °C.
  • MALDI-MS matrix assisted laser desorption ionization mass spectroscopy
  • MALDI-MS imaging was conducted on mouse skin strips after administration of bimatoprost or compound disclosed herein once daily for 3 days. Samples of mouse skin were recovered 4 hr after day-3 dosing of compound. Dermal administration was conducted with vehicle, 0.03% bimatoprost, 3% bimatoprost, 0.03% Compound IVa, and 3% Compound IVa.
  • Fig. 16A depicts a typical explanted sample of mouse skin for these studies, wherein Compound IVa was applied via dermal administration.
  • Fig. 16B depicts the result of MALDI-MS imaging. The intensity of each pixel within Fig. 16B reflects the concentration of Compound IVa at the corresponding point in the image depicted in Fig. 16A.
  • Fig. 16C depicts a representative mass spectrum, corresponding to the region of Fig. 16B indicated by the white circle within Fig. 16B . Accordingly, each pixel of the image of Fig. 16B has an associated mass spectrum, providing the amounts of bimatoprost or other administered compound or metabolite thereof.
  • MALDI-MS imaging is able to selectively detect Compound IVa and bimatoprost following topical dermal administration of 3.0% Compound IVa on mouse skin. Without wishing to be bound by any theory, it is believed that MALDI-MS imaging has sufficient sensitivity to detect bimatoprost and compounds disclosed herein upon topical dermal administration at 3% (w/w) dosage, or even greater sensitivity. Indeed, Compound IVa was detectable in the assay system after administration of Compound IVa at 0.03%, whereas vehicle control samples displayed no signal for Compound IVa.

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EP12705582.0A 2011-02-14 2012-02-13 Ester derivatives of bimatoprost compositions and methods Not-in-force EP2675786B1 (en)

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AU2012217922B2 (en) 2017-05-04
US20130324606A1 (en) 2013-12-05
CA2827446A1 (en) 2012-08-23
CN103459368B (zh) 2016-06-08
BR112013020719A2 (pt) 2016-08-09
CA2827446C (en) 2020-06-23
BR112013020719B1 (pt) 2018-04-17
RU2599249C2 (ru) 2016-10-10
JP5885271B2 (ja) 2016-03-15
US9499478B2 (en) 2016-11-22
TW201247613A (en) 2012-12-01
CN103459368A (zh) 2013-12-18
WO2012112451A1 (en) 2012-08-23
EP2675786A1 (en) 2013-12-25
JP2014513051A (ja) 2014-05-29
RU2013141849A (ru) 2015-03-27
AU2012217922A1 (en) 2013-09-05
US20150005377A1 (en) 2015-01-01
TWI642653B (zh) 2018-12-01
KR101935068B1 (ko) 2019-01-03
KR20140015364A (ko) 2014-02-06

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